1. Field of the Invention
This invention relates to a method of obtaining D-glucuronic acid. D-glucuronic acid and its derivatives (lactone, salts, amides, etc.) are biologically high-active compounds, which are widely used in medicine and pharmaceutical chemistry for the synthesis of modified drugs as well as food additives, skin-care preparations, and the like.
2. Discussion of Related Art
Most methods of obtaining D-glucuronic acid are based on 1,2-isopropylidene-D-glucose, during the oxidation of which 1,2-isopropylidene-D-glucuronic acid, or frequently the salts thereof (Na, K, Ca, Ba, etc.), is or are precipitated. The following steps are used to convert these compounds into glucuronic acid:
Glucuronic acid is distinguished for its high chemical instability and is suitable for many conversions under mild conditions. The tautomeric conversions into solutions (mutarotation), typical for monosaccharides, are more difficult with glucuronic acid because of the formation of D-glucofuranyrone-6,3-lactone (glucuronic acid lactone). The equilibrium ratio of the components at room temperature is 60% glucuronic acid and 40% glucuronic acid lactone. The increase in temperature and the presence of acid catalysts accelerate achieving this equilibrium. When heating D-glucuronic acid in the presence of strong acids, the decarboxylation also occurs easily with the formation of carbon dioxide, furfural and other products of decomposition. In the acidic, neutral and alkaline media, the glucuronic acid is converted into epimers according to C-2 and also into the respective ketonic acids and isomeric GK-aldehyde acids. This makes the processes for obtaining glucuronic acid (GS) more difficult and causes, in known methods, either the mixtures of GS or the salts of glucurone (GK) to be obtained.
A method of obtaining 1,2-isopropylidene-D-sodium glucuronate is known, for example from USSR No. 883054 M.Kl.3 C07H7/02 which is used as the intermediate product during the synthesis of D-glucuronic acid, the lactones thereof (glucurone) and the derivatives thereof, which are obtained by a catalytic oxidation of 1,2-isopropylidene-D-glucose with air oxygen in the weakly basic medium at a high temperature and by agitation. During the oxidation, the catalyst used is a palladium catalyst, which has 1.8% Pd relative to carbon, conveyed through potassium salts (0.8%) and sodium salts (0.2%) at a ratio between the compound to be oxidized and the catalyst of 1:0.45-0.91 at a temperature of 65-70° C., at a pH value of 7.5-8.0 and at a concentration of the starting substance of 1-10%.
However, D-glucuronic acid and glucuronic lactone cannot be obtained with this known method.
Another method of obtaining D-glucuronic acid is known from Mehltretter C. L., Alexander B. H., Mellies R. L. et al. “A Practical Synthesis of D-Glucuronic Acid through the Catalytic Oxidation of 1,2-isopropylidene-D-glucose”, J. Am. Chem. Soc., 1951, V. 73, No. 6, Pages 2424-2427. In this method, the water solution of Ca-isopropylidene glucuronic acid is heated at a temperature of 90-100° C. with an equimolecular quantity of the dihydrate of oxalic acid during a time period of 1.75 hours, and then the insoluble and precipitated calcium oxalate is filtered. After the removal of the water and after the reaction mass has been treated with ethanol, a mixture is obtained which contains 60% glucuronic acid and 40% glucuronic acid lactone (GK lactone).
This method has only limited operational possibilities, because it can only be used for calcium salts, or barium salts, of 1,2-0-isopropylidene-D-glucuronic acid, the neutralization and hydrolysis of which lead to insoluble calcium or barium oxalates, which can easily be separated from the GK solution and the GK lactone by filtering. The other salts of 1,2-0-isopropylidene-D-glucuronic acid, such as sodium or potassium, provide soluble oxalates which cannot be separated from the target product by the known methods.
One invention of particular relevance to the technical essence and to the object to be achieved with this invention is a method of obtaining D-glucuronic acid which is precipitated in the form of an Na salt, as taught by Feldmann D. P., Woytenko A. D., Shimaskaya M. B., etc. “Verfahren zur Gewinnung von D-Natriumglukuronat” [in translation: “Method of obtaining D-sodium glucuronate”], Chemie-Pharm. Magazin, 1984, No. 11, Pages 1356-1360. In this known method, the acetonation of the D-glucose is accomplished in the presence of sulphuric acid by forming a mixture of two principal products, namely 1,2-0-isopropylidene-D-glucuronic acid and 1,2;5,6-di-O-isopropylidene-D-glucuronic acid, the last compound being converted by an acid hydrolysis into 1,2-O-isopropylidene-D-glucose, and 1,2-O-isopropylidene-D-sodium glucuronate being obtained by the catalytic oxidation thereof. By the hydrolysis of such compound by heating to a temperature of 100° C. during the course of 2 hours and by the action of a 1% solution of hydrochloric acid and an additional neutralization by of sodium hydroxide and evaporation of the solution to its dry state, a mixture of D-sodium glucuronate and sodium chloride is obtained. The precipitation of the D-sodium glucuronate from the mixture is accomplished by a multiple extraction using hot dimethyl sulphoxide and a later addition of acetone to the extract, as well as by filtering the precipitating D-sodium glucuronate.
The operational possibilities of the known method are limited to the use of 1,2-O-isopropylidene-D-glucuronic acid for metals, which produce insoluble chlorides, such as NaCl, in dimethyl sulphoxide. When the developing chlorides are soluble in dimethyl sulphoxide, the cleaning of the D-glucuronic acid salt by the extraction is not possible by using hot dimethyl sulphoxide.
One disadvantage of the known method is that during the neutralization and hydrolysis of the Na-isopropylidene glucuronic acid by hydrochloric acid as the result of the instability of the D-glucuronic acid, secondary conversions occur which reduce the yield and render the cleaning processes of the target products more complex. In addition, the cleaning of the Na salt of D-glucuronic acid leads to elaborate and environmentally harmful operating sequences for the extraction by dimethyl sulphoxide, and furthermore to a deposition of the product with acetone.